Mutations in presenilin (PS1 and PS2) are linked to early onset of familial Alzheimer's disease (FAD). Presenilin is required for the processing of Notch and the b-amyloid precursor protein, molecules that play critical roles in development and AD pathogenesis respectively. In addition, PS1 associates with b-catenin, a multi-functional protein involved in Wnt signaling and cadherin/catenin-mediated cell adhesion. We reported that PS! down regulates b-catenin through this interaction. As such, loss of PS1 is associated with enhanced b-catenin signaling and tumorigenesis in mice. However, PS1 deficiency leads to simultaneous disruption of all presenilin activities and the definitive role of PS1-catenin pathway cannot be determined. Although PS1 -b-catenin interaction has been established, the role of PS2 in b-catenin regulation remains to be addressed. We recently discovered that PS2 facilitates PS1-mediated skin tumorigenesis. This calls for a need to systematically investigate the involvement of PS2 in b-catenin pathway. Directly relevant to AD, PS1 is localized at synaptic contacts and PS1 FAD mutant protein exhibits impaired b-catenin regulating activities, raising the possibility that an impaired b-catenin homeostasis may contribute to synaptic dysfunction, a hallmark intimately linked to AD dementia. The following hypotheses are formulated based on these findings: a) Presenilin-b-catenin association plays a central role in b-catenin signaling and cadherin/catenin-mediated cell adhesion in vivo. Deregulation of b-catenin is causal for loss-of-PS1-induced neoplasia and alters synaptic activity in the central nervous system; b) PS1FAD mutation leads defective b-catenin regulation and synaptic dysfunction; c) PS1 and PS2 cooperate to negatively regulate b-catenin. This application is aimed at testing these hypotheses using a novel biological tool we recently created: The PS1 knock-in mice with specific deletion of b-catenin interaction. This allele genetically separates the two important activities PS1 mediates, namely Notch and b-catenin, under in vivo physiological conditions, thus allowing us to definitely determine the role of PS1 -b-catenin pathway. The availability of the PS1M146V FAD knock-in mice makes it feasible to evaluate the effect of FAD mutation on b-catenin pathway. Further, the mechanisms of PS2 in b-catenin regulation will be investigated. The proposed study will lead to a comprehensive understanding of the molecular mechanisms of presenilin and the effect of FAD mutation on b-catenin regulation, tumorigenesis and synaptic formation and maintenance.